A5005042007- Pulmonary Hypertension Research and Treatments
- Cell Adhesion Molecules Research
- Ubiquitin and proteasome pathways
- Protein Kinase Regulation and GTPase Signaling
- Cellular transport and secretion
- Platelet Disorders and Treatments
- Caveolin-1 and cellular processes
- Retinal Diseases and Treatments
- Eosinophilic Disorders and Syndromes
- Nitric Oxide and Endothelin Effects
- Glaucoma and retinal disorders
- Traumatic Brain Injury and Neurovascular Disturbances
- RNA modifications and cancer
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Aortic aneurysm repair treatments
- Receptor Mechanisms and Signaling
- MicroRNA in disease regulation
- Protease and Inhibitor Mechanisms
- Microtubule and mitosis dynamics
- Protein Tyrosine Phosphatases
- Thermal Regulation in Medicine
- Blood disorders and treatments
- Hemodynamic Monitoring and Therapy
- Hippo pathway signaling and YAP/TAZ
- Cardiovascular Health and Disease Prevention
Hubrecht Institute for Developmental Biology and Stem Cell Research
2022-2023
University Medical Center Utrecht
2023
Amsterdam University Medical Centers
2019-2023
Vrije Universiteit Amsterdam
2019-2023
Amsterdam Neuroscience
2021
Amsterdam UMC Location Vrije Universiteit Amsterdam
2021
Sanquin
2017-2018
Amsterdam UMC Location University of Amsterdam
2017
University of Amsterdam
2017
Rationale: von Willebrand factor (vWF) mediates platelet adhesion during thrombosis. While chronic thromboembolic pulmonary hypertension (CTEPH) is associated with increased plasma levels of vWF, the role this protein in CTEPH has remained enigmatic. Objectives: To identify vWF CTEPH. Methods: CTEPH-specific patient and endarterectomy material from patients were used to study relationship between inflammation, expression, Cell culture findings validated human tissue, proteomics chromatin...
RhoGTPases control endothelial cell (EC) migration, adhesion, and barrier formation. Whereas the relevance of RhoA for function is widely accepted, role homologue RhoB poorly defined. are 85% identical, but RhoB’s subcellular localization half-life uniquely different. Here, we studied ubiquitination stability in primary human ECs. We show that K63 polyubiquitination at lysine 162 181 targets protein to lysosomes. Moreover, identified RING E3 ligase complex Cullin-3–Rbx1–KCTD10 as key...
Endothelial hyperpermeability following cardiopulmonary bypass (CPB) contributes to microcirculatory perfusion disturbances and postoperative complications after cardiac surgery. We investigated the course of renal pulmonary endothelial barrier function association with angiopoietin-2 levels in patients CPB. Clinical data, sublingual plasma samples were collected from undergoing coronary artery graft surgery CPB (n = 17) before at several time points up 72 h Renal microvascular cells...
RhoGTPases regulate cytoskeletal dynamics, migration and cell-cell adhesion in endothelial cells. Besides regulation at the level of guanine nucleotide binding, they also undergo post-translational modifications, for example ubiquitination. are ubiquitinated by Cullin RING ligases which turn regulated neddylation. Previously we showed that inhibition ligase activity neddylation inhibitor MLN4924 is detrimental barrier function, due to accumulation RhoB consequent induction contractility....
Considering its intolerance to ischemia, it is of critical importance for the brain efficiently process microvascular occlusions and maintain tissue perfusion. In addition collateral flow enzymatic degradation emboli, endothelium has potential engulf microparticles thereby recanalize vessel, through a called angiophagy. Here, we set out study dynamics angiophagy in relation cytoskeletal remodeling vitro reperfusion vivo. We show that polystyrene microspheres fibrin clots are actively taken...
Signaling by the Rho GTPase Rac1 is key to regulation of cytoskeletal dynamics, cell spreading and adhesion. It widely accepted that inactive form bound GDI, which prevents activation Rac1-effector interactions. In addition, GDI-bound protected from proteasomal degradation, in line with data showing ubiquitination occurs exclusively when activated. We set out investigate how activity, GDI binding are linked. introduced single amino acid mutations differentially altered compared whether level...
Abstract Inflammation is driven by excessive transmigration (diapedesis) of leukocytes from the blood to tissue across endothelial cell monolayer that lines vessels. Leukocyte adhesion, crawling, and are regulated clustering mechanosensitive receptor intercellular adhesion molecule-1 (ICAM-1). Whereas several proteins known promote ICAM-1 function, molecular mechanisms limit ICAM-1–mediated prevent leukocyte remain unknown. We identify actin-binding protein CD2-associated (CD2AP) as a novel...
Rho GTPases control both the actin cytoskeleton and adherens junction stability are recognized as essential regulators of endothelial barrier function. They act molecular switches primarily regulated by exchange GDP GTP. However, posttranslational modifications such phosphorylation, prenylation, ubiquitination can additionally alter their localization, stability, activity. F-box proteins involved in recognition substrate predestined for subsequent degradation. Given importance...
Three decades of research have documented the spatiotemporal dynamics RHO family GTPase membrane extraction regulated by guanine nucleotide dissociation inhibitors (GDIs), but interplay kinetic mechanism and structural specificity these interactions is as yet unresolved. To address this, we reconstituted GDI-controlled spatial segregation geranylgeranylated protein RAC1 in vitro. Various biochemical biophysical measurements provided unprecedented mechanistic details for GDI function with...
Endothelial monolayer permeability is regulated by actin dynamics and vesicular traffic. Recently, ubiquitination was also implicated in the integrity of quiescent endothelium, as it differentially controls localization stability adhesion signaling proteins. However, more general effect fast protein turnover on endothelial not clear. Here, we found that inhibition E1 ubiquitin ligases induces a rapid, reversible loss quiescent, primary human monolayers, accompanied increased F-actin stress...
Abdominal aortic aneurysms (AAAs) are associated with overall high mortality in case of rupture. Since the pathophysiology is unclear, no adequate pharmacological therapy exists. Smooth muscle cells (SMCs) dysfunction and extracellular matrix (ECM) degradation have been proposed as underlying causes. We investigated SMC spatial organization SMC-ECM interactions our novel 3-dimensional (3D) vascular model. validated model for future use by comparing it to existing 2-dimensional (2D) cell...
<b>Background:</b> Endothelial von Willebrand Factor (VWF) plays a key role in platelet recruitment during thrombosis at the vessel wall. Plasma VWF levels are elevated patients with chronic thromboembolic pulmonary hypertension (CTEPH). Whether local endothelial production and <i>in situ</i> play development of CTEPH remains unknown. The present study investigates possible contribution cells to CTEPH. <b>Methods:</b> Freshly isolated platelets healthy subjects were perfused over human...
Summary Endothelial monolayer permeability is regulated by actin dynamics and vesicular traffic. Recently, ubiquitination was also implicated in the integrity of quiescent endothelium, as it differentially controls localization stability adhesion- signaling proteins. We found that inhibition E1 ubiquitin ligases induces a rapid, reversible loss quiescent, primary human endothelial monolayers, accompanied increased F-actin stress fibers formation intercellular gaps. Concomitantly, total...
Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by obstructions of the circulation; disease progression may involve in situ thrombosis. CTEPH patients have elevated Von Willebrand Factor (VWF) plasma levels and we hypothesized that endothelial secretion VWF recruits platelets to vascular wall, thereby driving Methods: specific primary artery cells (PAEC) were isolated from endarterectomy material control PAECs undergoing lobectomy. Endothelial-platelet...